Pancreatic neoplasia is the fifth most common cancer in the United States. Its etiology is largely unknown and no curative treatment is presently available. Over-expression of epidermal growth factor receptor (EGFR) occurs in approximately 90% of human pancreatic cancer. EGFR over-expression or activation leads to the activation of Akt and NF-kappaB signaling pathways, suggesting that these pathways are important therapeutic targets for pancreas cancer. Activation of Akt/NF-kappaB in pancreatic cancer induces downstream target genes, such as uPA, VEGF, IL-8 and Bcl-xl that may mediate its cardinal clinical features of locally aggressive growth, metastasis, and chemotherapy resistance. We have recently observed that genistein is a potent inhibitor of Akt/NF-kappaB pathway and inducer of apoptotic cell death. Our microarray data from cells treated with genistein showed inactivation of NF-kappaB downstream genes that are important in angiogenesis, invasion and metastasis (Cancer Letters 186:157, 2002). In addition, we have recently discovered a new cDNA that codes for ERRP. ERRP is believed to attenuate the EGFR function by sequestration of EGFR ligands, and that the ERRP could be upregulated by genistein treatment of pancreatic cancer cells. Our results also suggest that treatment of pancreatic cancer cells with either genistein or ERRP or their combinations may induce apoptotic cell death, and may also sensitize pancreatic cancer cells to commonly used chemotherapeutic agents, such as cisplatin and gemcitabine. Collectively, these findings strongly suggest that the inactivation of the EGFR/Akt/NF-kappaB pathways should be very important for devising therapeutic strategies for pancreatic cancer, which could be accomplished by our novel approach (genistein and ERRP treatment). Based on our preliminary data, we hypothesize that ERRP is a negative regulator of EGFR that inhibits proliferation and stimulates apoptosis by attenuating EGFR signaling. We further hypothesize that inactivation of Akt/NF-kappaB signaling, which is a downstream signaling pathway of EGFR, by genistein may potentiate the activity of ERRP treatment in pancreatic cancer cells, and may also sensitize these cells to cisplatin and/or gemcitabine. To test our hypothesis, we will determine how ERRP inactivates EGFR signaling, and also determine the effects of ERRP and genistein on cell growth inhibition and induction of apoptosis, and correlate these results with inactivation of Akt and NF-kappaB. Moreover, we will determine the cause and effect relationships between cell growth inhibition and apoptosis inducing activity of genistein and ERRP with Akt/NF-kappaB signaling, by gene transfection experiments. We will also test whether the inactivation of Akt/NF-kappaB by genistein and/or ERRP could sensitize pancreatic cancer cells to cisplatin and gemcitabine-induced apoptosis. Finally, we will test whether the treatment effects of these agents alone or in combinations with or without cisplatin and gemcitabine will inhibit tumor growth in SCID xenografts. These results will provide mechanistic as well as pre-clinical data in support of our hypotheses and may open new and novel avenues for the treatment of human pancreatic cancer.